The present invention relates to a novel pharmaceutical composition wherein at least one cyclosporin is the active ingredient and is accompanied by a solubilising agent which is .alpha.-cyclodextrin and/or a derivative thereof.
The cyclosporins are a homologous group of biologically active oligopeptides, which are metabolites produced by certain fungi imperfecti. Cyclosporin A is the best known member of this group, but cyclosporins B to I have also so far been identified, and the commercially available product may contain a mixture of several individual cyclosporins. They all share a cyclic peptide structure consisting of 11 amino acid residues with a total molecular weight of about 1,200, but with different substituents or configuration of some of the amino acids.
For convenience, the term "cyclosporin" (in the singular and without further qualification) will be used hereinafter to designate the cyclosporin component in the composition of the present invention. However, it should be understood that, as used with reference to the invention, this term is intended to include any individual member of the cyclosporin group, as well as mixtures of two or more such individual cyclosporins whether in the form of commercially available mixtures or otherwise.
Cyclosporin has immunosuppressive, antifungal and antiphlogistic activities, but has so far been primarily used therapeutically for its immunosuppressive activity. In its therapeutic use as an immunosuppressive, it is currently used either orally or by injection. However, since the solubility of cyclosporin in water is extremely low (e.g. 20 .mu.g/ml to 30 .mu.g/ml for cyclosporin A), both types of formulation are prepared as an oily solution containing ethanol. Even so, the bioavailability of its oral preparations is extremely low, generally below 30% [K. Takada et al, Drug Delivery System 1, No. 1, 1-7 (1986)]. This is believed to be due to the separation of cyclosporin as a solid immediately after it comes into contact with water, e.g. in the mouth or in the gut. Injectable preparations of cyclosporin formed as an oily solution containing ethanol have first to be diluted with physiological saline before intravenous administration. In the case of intravenous administration, however, it is clearly not merely undesirable, but highly dangerous for cyclosporin to separate out on contact with water. Accordingly, a surface active agent, such as a polyoxyethylated castor oil, is added as a solubilizer to injectable preparations in order to prevent the cyclosporin from separating out. However, the addition of surface active agents, such as polyoxyethylated castor oil, to injectable preparations can give rise to safety problems.
Cyclosporin is effective in the treatment of the ocular symptoms of Behcet's Syndrome. If it is administered orally for the treatment of these symptoms and relies upon systemic circulation to reach the eyes, the side effects of the drug may cause various adverse reactions, such as hypertrichosis or renal dysfunction. However, if oily preparations containing cyclosporin are applied directly to the eyes, irritation or a clouded visual field may result. Hence, cyclosporin is, in practice, of little practical use in the treatment of the ocular symptoms of Behcet's Syndrome, for which it would otherwise be well suited. Moreover, if it were possible to prepare a formulation suitable for topical application to the eyes, it would be expected to have various other uses in addition to the treatment of the ocular symptoms of Behcet's Syndrome. For example, from its pharmacological mode of action, it is though that it could be useful during keratoplasty, as well as in the treatment of herpetic keratitis and spring catarrh.
One way of overcoming this problem would be to dissolve sufficient cyclosporin in an aqueous solvent system so as to reach an effective concentration for treatment. Such a solvent system should not contain any additive, such as a surface active agent, which could give rise to safety problems. If this could be achieved, the cyclosporin would already be in an aqueous solution and its contact with bodily fluids would merely constitute dilution, so that it would not immediately separate out when contacted with the water of such fluids. However, so far it has been very difficult to make any such preparation because cyclosporin has an extremely low solubility in water and has a cyclic structure with a molecular weight significantly greater than 1,000, with the result that a sufficient amount cannot be dissolved to be effective for the desired treatment. For instance, Table 1 shows the solubility of cyclosporin A in various kinds of solvents, from which it can be seen that the solubility pattern seems quite unique.
TABLE 1 ______________________________________ Solubility of Solubility parameters cyclosporin A Solvent .delta.d .delta.p .delta.h [mg/ml] ______________________________________ Methanol 7.4 6.0 10.9 &gt;1000 Ethanol 7.7 4.3 9.5 &gt;1000 Acetonitrile 7.5 8.8 3.0 &gt;1000 Ethyl acetate 7.4 2.6 4.5 &gt;1000 Benzene 8.9 0.5 1.0 400 Tetrahydrofuran 8.2 2.8 3.9 400 Acetone 7.6 5.1 3.4 100 Propylene glycol 8.2 4.6 11.4 100 Isopropanol 7.7 3.0 8.0 50 Cyclohexane 8.2 0.0 0.0 20 Hexane 7.2 0.0 0.0 &lt;10 Water 6.0 15.3 16.7 &lt;1 ______________________________________
In the above Table, .delta.d, .delta.p and .delta.h are measures of dispersion force, polarity and hydrogen bonding, respectively.
In view of these solubility properties, it has, in the past, been considered not merely difficult, but practically impossible to prepare a pharmaceutical composition containing cyclosporin dissolved in an aqueous medium.
We have now surprisingly found that this long-felt want can be met by incorporating .alpha.-cyclodextrin into a pharmaceutical preparation.